Methods for treating overweight or obesity

ABSTRACT

The present invention relates to methods of managing weight, and treating overweight or obesity and treating or preventing diabetes in a subject in need thereof. In one embodiment, the method comprises the steps of (a) orally administering to the subject from about 0.7 g to about 4 g of crosslinked carboxymethylcellulose; and (b) orally administering to the subject at least about 100 mL of water per gram of crosslinked carboxymethylcellulose. Steps (a) and (b) are conducted prior to or with at least one meal per day.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.62/014,926, filed on Jun. 20, 2014. The entire teachings of the aboveapplication are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Public health efforts and current anti-obesity agents have notcontrolled the obesity epidemic. This disorder is increasingly prevalentin industrialized nations because of the abundance of food and thereduced activity levels that accompany the movement of populations fromrural to urban settings. Obesity is loosely defined as an excess of bodyfat over that needed to maintain health.

Obesity is a condition in which excess body fat has accumulated to suchan extent that health may be negatively affected. (World HealthOrganization (2000)). (Technical report series 894: Obesity: Preventingand managing the global epidemic). It is commonly defined as a Body MassIndex (BMI=weight divided by height squared) of 30 kg/m² or higher.Overweight is distinguished and defined as a BMI between 25-29.9 kg/m²(Obes Res. 1998 September; 6 Suppl 2:51S-209S. (Clinical Guidelines onthe Identification, Evaluation, and Treatment of Overweight and Obesityin Adults—The Evidence Report. National Institutes of Health).

Excessive body weight is associated with various diseases, particularlycardiovascular diseases, diabetes mellitus type 2, obstructive sleepapnea, certain types of cancer, and osteoarthritis (National Heart,Lung, and Blood Institute. Clinical Guidelines on the Identification,Evaluation, and Treatment of Overweight and Obesity in Adults NIHPublication No. 98-4083 September 1998 National Institutes of Health).As a result, obesity has been found to reduce life expectancy. Theprimary treatment for obesity is dieting and physical exercise. If dietand exercise fails, anti-obesity drugs and bariatric surgery may berecommended in severe cases (National Institute for Health and ClinicalExcellence. Clinical Guideline 43: Obesity: The prevention,identification, assessment and management of overweight and obesity inadults and children. London, 2006).

The pathogenesis of obesity is multi-factorial and includes the controlof feeding behavior, mechanisms of fat storage, the components of energyintake and expenditure, and genetic and psychological influences.Likewise, the treatment of obesity is generally multi-factorial.Unfortunately, the mechanisms of fat storage and genetic influences arenot, generally speaking, amenable to treatment. Moreover, the control offeeding behavior and psychological influences require prolongedtreatment. Although the components of energy intake and expenditure aretreatable, many obese individuals are resistant to or incapable ofengaging in activities which significantly increase their energyexpenditure. Therefore, controlling energy intake is an attractiveapproach for the treatment of obesity.

There is a need for new methods for managing weight and preventing ortreating overweight and obesity. Further, treatments for obesity aretypically no more effective in diabetic patients than in nondiabeticpatients and are often less effective (see, for example: Baker et al.,Met. Clin. Exper. 2012, 61:873; Scheen et al., Lancet 2006, 368:95489,1660; Pi-Sunyer et al., J. Am. Med. Assoc. 2006, 295:7, 761; Khan etal., Obes. Res. 2000, 8:1, 43; Guare et al., Obes. Res. 1995, 3:4, 329;Wing et al., Diabetes Care 1987, 10:5, 563). Thus there is a need forweight loss agents and methods which are particularly effective intreating diabetic patients. In addition, there is a need for effectivemethods for weight loss in prediabetics and for improving their healtheven in the absence of weight loss, for example, converting prediabeticsto nondiabetics.

SUMMARY OF THE INVENTION

The present invention relates to methods of inducing weight loss,managing weight, and treating overweight or obesity and treating orpreventing diabetes in a subject in need thereof. In one embodiment, themethod comprises the steps of (a) orally administering to the subjectfrom about 0.7 g to about 4 g of crosslinked carboxymethylcellulose; and(b) orally administering to the subject at least about 100 mL of waterper gram of crosslinked carboxymethylcellulose. Steps (a) and (b) areconducted prior to or with at least one meal per day.

In another embodiment, the invention provides a method for treating orpreventing diabetes or improving glycemic control in a subject. Themethod comprises orally administering to the subject from about 0.7 g toabout 4 g of crosslinked carboxymethylcellulose. This method isconducted prior to or with at least one meal per day.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the change in body weight (% change frombaseline, mean±SEM) for the placebo, CMC/CA 2.25 g and CMC/CA 3.75 ggroups over the course of the study described in Example 2.

FIG. 2A is a graph showing the relation between fasting blood glucose atbaseline and body weight change over the course of the study describedin Example 2 for the CMC/CA 2.25 g arm.

FIG. 2B is a graph showing the relation between fasting blood glucose atbaseline and body weight change over the course of the study describedin Example 2 for the placebo group.

FIG. 3 is a graph showing conversion of obese status to overweightstatus (% of subjects) in the placebo (n=30), CMC/CA 2.25 g (n=28) andCMC/CA 3.75 g (n=29) groups over the course of the study described inExample 2.

FIG. 4 is a graph showing conversion of overweight status to normalweight status (% of subjects) in the placebo (n=12), CMC/CA 2.25 g(n=14) and CMC/CA 3.75 g (n=12) groups over the course of the studydescribed in Example 2.

FIG. 5 is a graph showing conversion of impaired fasting blood glucosestatus to normal fasting blood glucose status (% of subjects) in theplacebo (n=11), CMC/CA 2.25 g (n=9) and CMC/CA 3.75 g (n=9) groups overthe course of the study described in Example 2.

FIG. 6 is a graph showing change in serum insulin concentration (%change from baseline) in the placebo (n=42), CMC/CA 2.25 g (n=41) andCMC/CA 3.75 g (n=37) groups over the course of the study described inExample 2.

FIG. 7 is a graph showing the change in insulin resistance (% changefrom baseline) by homeostatic model assessment in the placebo (n=42),CMC/CA 2.25 g (n=41) and CMC/CA 3.75 g (n=37) groups over the course ofthe study described in Example 2.

FIG. 8 is a graph showing the change in fasting blood glucose (% changefrom baseline) in the placebo (n=42), CMC/CA 2.25 g (n=41) and CMC/CA3.75 g (n=39) groups over the course of the study described in Example2.

FIG. 9 is a graph showing the change in total energy intake (change frombaseline, %, mean±SEM) in subjects with elevated fasting blood glucose(>93 mg/dL) at baseline in the placebo (n=21), 2.25 g CMC/CA (n=21) and3.75 g CMC/CA (n=14) groups over the course of the study described inExample 2.

FIG. 10 is a graph showing the change in energy intake fromcarbohydrate, fat and protein (change from baseline, %, mean±SEM) insubjects with elevated fasting blood glucose (>93 mg/dL) at baseline inthe placebo (n=21), 2.25 g CMC/CA (n=21) and 3.75 g CMC/CA (n=14) groupsover the course of the study described in Example 2.

DETAILED DESCRIPTION OF THE INVENTION

The methods of the invention are of use in inducing weight loss,maintaining weight, treating or preventing diabetes and/or improvingglycemic control in a subject in need thereof. In particular, themethods of the invention are useful for inducing weight loss in subjectshaving elevated fasting blood glucose levels prior to treatment,prediabetic subjects and diabetic subjects. In certain embodiments, themethods are useful for lowering the fasting blood glucose of a subjectfrom a level indicative of prediabetes to a normal level.

Methods for Inducing Weight Loss

In one embodiment, the invention provides a method for inducing weightloss in an overweight or obese subject, particularly in subjects havingelevated fasting blood glucose levels, prediabetic subjects and diabeticsubjects.

The method can be used to treat obesity or overweight. The method canalso be used to manage or maintain weight, i.e., prevent or inhibitweight gain, in a subject who is of normal weight or is overweight. Thepresent methods are particularly effective in inducing weight loss inprediabetic and diabetic subjects.

In one embodiment, the method of the invention for inducing weight losscomprises the steps of (a) orally administering to the subject fromabout 0.7 to 4 g of crosslinked carboxymethylcellulose; and (b) orallyadministering to the subject at least about 100 mL of water per gram ofcrosslinked carboxymethylcellulose. In one embodiment, method steps (a)and (b) are conducted prior to or with at least one meal per day. Incertain embodiments, method steps (a) and (b) are conducted prior to orwith two meals per day. In certain embodiments, method steps (a) and (b)are conducted prior to or with three meals per day. In certainembodiments, the subject is directed to eat four or more meals per day,and method steps (a) and (b) are conducted prior to or with at least onemeal per day, at least two meals per day, at least 3 meals per day or atleast 4 meals per day. In other embodiments, steps (a) and (b) areconducted prior to or with every meal of the day.

The method of the invention is preferably conducted daily for a periodof days sufficient to achieve a significant weight loss. For example,the method can be conducted daily until a desired or beneficial amountof weight loss. In certain embodiments, the treatment is continued untilthe subject has lost a predetermined amount of weight. Preferably, thesubject has lost 3 to 20% of his or her initial body weight, preferablyat least 5%. In one embodiment, the method is conducted daily until thesubject has lost from 5 to 15% of his or her initial body weight. Forexample, the method can be conducted daily up to one week, up to fourweeks, up to eight weeks, up to twelve weeks, up to sixteen weeks, up totwenty weeks, up to twenty-four weeks, up to 36 weeks, or up to one yearor longer. In some embodiments, the method is conducted chronically,i.e., for a period of greater than one year or for an indefinite period.In some embodiments, the method is conducted daily for a first period oftime, stopped for a second period and then conducted for a third periodof time. This alternation of treatment periods and nontreatment periodscan be conducted over multiple cycles or continued indefinitely.

In one embodiment, the amount of crosslinked carboxymethylcelluloseadministered in step (a) is from about 0.7 g to about 4 g, or about 0.7g to about 3 g. In certain embodiments, the amount of crosslinkedcarboxymethylcellulose administered in step (a) is from about 1.1 g toabout 3 g, from about 1.5 g to about 3.0 g, from about 1.8 g to about3.0 g or from about 1.75 g to about 2.75 g. In certain embodiments, theamount of crosslinked carboxymethylcellulose is from 1.9 to 2.5 g or 2.0to 2.5 g. In certain embodiments, the amount of crosslinkedcarboxymethylcellulose is from 2.0 to 2.35 g or 2.15 to 2.35 g. Incertain embodiments, the amount of crosslinked carboxymethylcellulose isabout 2.25 g.

The amount of water administered in step (b) is preferably at leastabout 100 mL per gram of crosslinked carboxymethylcellulose, and is morepreferably at least about 150 mL per gram of crosslinkedcarboxymethylcellulose. In certain embodiments, the amount of wateradministered is from about 150 mL to about 250 mL per gram ofcrosslinked carboxymethylcellulose. In certain embodiments the amount ofwater administered is at least about 175 mL per gram of crosslinkedcarboxymethylcellulose. In other embodiments, the amount of wateradministered at least about 200 mL per gram of crosslinkedcarboxymethylcellulose. In certain embodiments, the amount of wateradministered is at least about 400 mL. In certain embodiments, theamount of water administered is at least about 450 mL, 475 mL or 500 mLto 550 mL.

Although there is no upper limit on the amount of water to beadministered, preferably the amount of water administered and/or therate at which the water is consumed does not cause the subjectdiscomfort.

Method steps (a) and (b) are preferably conducted at a time prior to orconcurrently with the meal which is sufficient for significant swellingof the crosslinked carboxymethylcellulose in the stomach of the subject.In one embodiment, step (a) is conducted from 0 to 50 minutes prior tothe meal. In another embodiment, step (a) is conducted from 15 to 40minutes prior to the meal. Preferably, step (a) is conducted from 20 to30 minutes prior to the meal. In one embodiment, step (b) is conductedfrom 0 to 20 minutes after step (a). In another embodiment, step (b) isconducted from 3 to 15 minutes after step (a). Preferably, step (b) isconducted from about 3 to about 10 minutes or 3 to 7 minutes after step(a). In one embodiment, step (b) is begun simultaneously with step (a)and administration of water can continue for period of time sufficientfor the subject to comfortably consume the water and can continue intothe meal, for example, until halfway through the meal.

The present method of treatment is optionally administered incombination with a hypocaloric diet, i.e., a diet providing fewer thanthe required calories for the subject. The estimated caloric requirementfor a given subject can be determined using methods known in the art andwill depend on factors such as gender, age and weight. In oneembodiment, the hypocaloric diet provides fewer than 2000 kcal of energyper day. Preferably, the hypocaloric diet provides from 1200 to 2000kcal per day. In one embodiment, the subject consumes a diet whichprovides a deficit of at least 100, 200, 300, 400, 500 or 600 kcal perday. A hypocaloric diet can be administered temporarily or throughoutthe course of treatment.

In one embodiment, steps (a) and (b) are conducted prior to or with onemeal per day and the daily amount of crosslinked carboxymethylcelluloseis from about 1.1 g to about 2.25 g. In one embodiment, steps (a) and(b) are conducted prior to or with two meals per day and the dailyamount of crosslinked carboxymethylcellulose is from about 1.1 g toabout 4.5 g, preferably from about 2.2 g to 4.5 g. In one embodiment,steps (a) and (b) are conducted prior to or with three meals per day andthe daily amount of crosslinked carboxymethylcellulose is from about1.65 g to about 6.75 g, preferably from about 3.3 g to about 6.75 g. Inone embodiment, steps (a) and (b) are conducted prior to or with fourmeals per day and the daily amount of crosslinked carboxymethylcelluloseis from about 2.2 g to about 6 g or 2.2 g to about 9 g, preferably fromabout 4.4 g to about 6 g or 4.4 g to about 9 g.

In another embodiment, the method of the invention is useful formaintaining a desired weight, for example, by inhibiting weight gain bya subject. In one embodiment, the subject has lost weight using themethod of the invention and is then placed on a maintenance dose of thecrosslinked carboxymethylcellulose. The subject can be of normal weightor overweight, but susceptible to weight gain. In certain embodiments,the amounts of crosslinked carboxymethylcellulose and water administeredand the frequency of administration are as described above. In anotherembodiment, the amount of crosslinked carboxymethylcelluloseadministered is lower and/or is administered fewer times per daycompared to use of the method to induce weight loss. In certainembodiments, the method is conducted prior to or with one meal per day.In another embodiment, the amount of crosslinked carboxymethylcelluloseadministered is step (a) is from about 0.7 g to about 2.0 g. The amountof water administered in step (b) is at least about 100 mL per gram ofcrosslinked carboxymethylcellulose. In certain embodiments the amount ofwater is at least about 125 mL or at least about 150 mL per gram ofcrosslinked carboxymethylcellulose. In other embodiments, the amount ofwater administered is at least about 200 mL per gram of crosslinkedcarboxymethylcellulose. In certain embodiments, the amount of wateradministered is from about 125 mL to about 500 mL or from about 125 mLto about 600 mL. In certain embodiments, the amount of wateradministered is from 150 mL to 575 mL, from 150 mL to 475 mL, from 200mL to 550 mL, from 200 mL to 450 mL, from 250 mL to 500 mL or from 200mL to 400 mL.

The water administered in step (b) can be flat or carbonated water, orin the form of a beverage. Preferably, non-carbonated water isadministered. In embodiments in which the water is administered as abeverage, the beverage preferably has pH of about 3 or higher, and morepreferably a neutral pH, i.e., a pH between 6 and 8, for example, a pHof about 6.5 to about 7.5, or about 7. Preferably, the beverage has anenergy content in the volume administered of 100 kilocalories or less or50 kilocalories or less. Preferably, the beverage is sugar free. In apreferred embodiment, the water is administered as drinking water, suchas tap water, spring water, or purified water.

The subject to be treated is a human or a nonhuman, such as a nonhumanmammal. Suitable nonhuman mammals include domesticated mammals, such aspets, including dogs and cats. Preferably, the subject is a human. Thesubject can be male or female. The human subject can be of any age, forexample, a child, adolescent or adult, but is preferably at least 10 orat least 12 years of age. In one embodiment, the subject is at least 18years old. When the subject is a child, the dose of crosslinkedcarboxymethylcellulose is preferably decreased in proportion with thesubject's weight.

The subject can be, for example, a human subject for whom weight losswill bring health benefits, such as human who is overweight, with a bodymass index of 25 to 29.9, or obese, with a body mass index of 30 orhigher. The subject can also be a human of normal weight, with a bodymass index of 18.5 to 24.9, but at risk of unhealthy weight increase. Ahuman subject can also have one or more other conditions orcomorbidities, such as prediabetes, diabetes or heart disease, inaddition to being overweight or obese. For example, the subject can haveone or more of the following: hypertension, such as blood pressure of140/90 mm Hg or higher; high LDL cholesterol; low HDL cholesterol, forexample less than 35 mg/dL; high triglycerides, for example higher than250 mg/dL; high fasting blood glucose, for example, a baseline level of≧100 mg/dl; a family history of premature heart disease; physicalinactivity; and cigarette smoking

In one embodiment, the human subject is prediabetic, as determined byone or more of fasting blood glucose level, A1C level and oral glucosetolerance test, according to the criteria established by the AmericanDiabetes Association (Diabetes Care 2004, 27:S15-35). For example, aprediabetic subject can have a fasting blood glucose level of 100 mg/dLto 125.9 mg/dL, an A1C level of 5.7 to 6.4% and/or an oral glucosetolerance test result of 140 to 199 mg/dL. Preferably, the prediabeticpatient has a baseline fasting blood glucose level of 100 mg/dL to 125.9mg/dL.

In another embodiment, the human subject is diabetic, as determined byone or more of fasting blood glucose level, A1C level and oral glucosetolerance test. For example, a diabetic subject can have a fasting bloodglucose level of 126 mg/dL or higher, an A1C level of 6.5% or higherand/or an oral glucose tolerance test result of 200 mg/dL or higher.Preferably, the diabetic patient has a fasting blood glucose level of126 mg/dL or higher.

In another embodiment, the subject has metabolic syndrome, as diagnosedusing the criteria set forth by the American Heart Association in 2004(Grundy SM, et al., Circulation. 2004; 109:433-438). According to theseguidelines, a subject is diagnosed with metabolic syndrome if at leastthree of the following five conditions are present: (1) elevated waistcircumference (men: >40 inches; women: >35 inches); (2) elevatedtriglycerides (150 mg/dL or higher); (3) reduced HDL cholesterol (men:less than 40 mg/dL; women: less than 50 mg/dL); (4) elevated bloodpressure (130/85 mm Hg or higher) or use of medication for hypertension;(5) fasting blood glucose ≧100 mg/dL or use of medication forhyperglycemia.

In another embodiment, the human subject has an elevated baselinefasting blood glucose level, for example, of about 90 mg/dL or higher orabout 93 or 95 mg/dL or higher. Subjects with fasting blood glucoselevels in this range include those with fasting blood glucose levels atthe high end of the normal range (90 to under 100 mg/dL), prediabetics(blood glucose levels of 100-125.9 mg/dL) and diabetics (blood glucoselevels of 126 mg/dL or higher).

It is to be understood that the measurements described above arebaseline measurements, that is, the values of the disclosedphysiological parameters prior to initiating a method of treatment asdescribed herein. More preferably, such measurements are made in theabsence of therapy intended to lower fasting blood glucose levels.Preferably, one or more of these values are determined within about ayear of the beginning of treatment according to the invention, morepreferably within about six months, even more preferably within aboutthree months and most preferably within about one month.

In another embodiment, the invention provides a method of inducingweight loss in a subject, such as a human subject as described above,wherein the subject has elevated blood glucose at baseline, isprediabetic or is diabetic. The method comprises the step of orallyadministering to the subject an effective amount of a gelling agent.Preferably the subject is a human having a baseline fasting bloodglucose level of about 90 mg/dL or higher or about 93 or 95 mg/dL orhigher. In certain embodiments, the subject has a baseline fasting bloodglucose level of 100 to 125.9 mg/dL or greater than 126 mg/dL.

In one embodiment, the method comprises orally administering to thesubject an effective amount of a gelling agent prior to or concurrentlywith a meal.

Suitable gelling agents for use in this method include, but are notlimited to, fibers, such as dietary fibers, and hydrogels, includingboth chemically and physically crosslinked absorbent polymers.Particularly suitable hydrogels include superabsorbent polymers. Amongthese, superabsorbants which are produced using food grade polymers arepreferred. For example, suitable gelling agents include polysaccharidesand synthetic polymers. Examples of suitable polysaccahrides includeglucans, including alpha-glucans, such as starch, dextran, pullulan, andglycogen; beta-glucans, such as cellulose or cellulose derivatives, suchas carboxymethylcellulose, hydroxyethylcellulose and methylcellulose,chrysolaminarin, curdlan, laminarin, lentinan, lichenin, pleuran, andzymosan; hemicelluloses, such as glucomannan, arabinoxylan, xylan,glucuronoxylan, and xyloglucan; galactomannans, such as guar gum,fenugreek gum, tara gum, and locust bean gum; pectins; fructans, such asinulin and levan; seaweed gums, such as alginates, algalpolysaccharides, agar, and carrageenan; chitin; chitosan;glycosaminoglycans, such as hyaluronic acid, heparin, heparan sulfate,chondroitin sulfate, dermatan sulfate, and keratan sulfate. Each of theforegoing polysaccharides is optionally physically or chemicallycrosslinked. In one embodiment, the gelling agent is not crosslinkedcarboxymethylcellulose. In another embodiment, the gelling agent is notcitric acid crosslinked carboxymethylcellulose.

Examples of suitable synthetic polymers include poly(ethylene glycol)based polymers; acrylates and acrylate copolymers, such aspolyacrylate/polyalcohol copolymers, polyacrylate/polyacrylamidecopolymers, crosslinked sodium polyacrylate; polyalcohol polymers, andcombinations thereof; polyacrylamide and acrylamide-based products;combinations of gums, such as polyisobutylene, styrene butadiene rubber,and similar with hydrophilic polymers; absorbent polypeptides, such assynthetic proteins generated starting directly from a small number (2 or3) of amino acids; polyvinyl and polyallyl-alcohol systems, such aspolyvinylacetate/vinylalcohol copolymers, crosslinked polyvinylpyrrolidone; polyamines, such as polyallyl amine, cross-linked with anybifunctional reagent with a double bond, such as a polyolefin; absorbentdendrimers; and poly(lactic acid), polyhydroxyalkanoates, polyvinylacetatephthalate and copolymers and combinations thereof.

Without being bound by theory, it is believed that such gelling agentsretard and/or reduce the uptake of glucose from food. Depending on itsstructure and degree of swelling in the gastrointestinal tract, thegelling agent is believed to form a diffusion barrier and/or topartially delay the absorption of glucose. For these reasons, it isbelieved that the hydration kinetics and extent of the gel in thedifferent sections of the gastrointestinal tract play a fundamental rolein retarding glucose absorption. Thus, the faster the hydration kineticsand the greater the extent of the gel, the more effective the gel willbe. A mild retardation effect is expected for loose fibers and thoseable to hydrate with slow kinetics and to only a limited extent. Greaterglucose retardation is expected to be achieved by crosslinked hydrogels,particularly by superabsorbent hydrogels.

The methods of inducing weight loss and treating overweight or obesityof the invention, as described above, are particularly useful insubjects having elevated baseline fasting blood glucose, includingprediabetic and diabetic subjects. Thus, a subject's fasting bloodglucose level indicates whether the subject is likely to particularlybenefit from treatment. In one embodiment, the methods for inducingweight loss of the invention further include the step of identifying asubject to receive the treatment according to one of the disclosedmethods, prior to the initiation of treatment. This step comprisesdetermining the baseline fasting blood glucose level of the subject,wherein if the subject has an elevated baseline fasting blood glucoselevel, as defined above, the subject is treated according to a method ofinducing weight loss as described herein.

In another embodiment, the invention provides a method of modifying themacronutrient preferences of a subject with elevated fasting bloodglucose at baseline. The method comprises regulating the blood glucoselevel of the subject. In one embodiment, the method comprisesadministering to the subject an effective amount of an agent whichimproves glycemic control. The agent can be crosslinkedcarboxymethylcellulose or a gelling agent as described above, which isorally administered. The term “macronutrients” as used herein, refers tocarbohydrates, fats and protein. In a preferred embodiment, the methodresults in reduced consumption of carbohydrates and, preferably,increased consumption of protein. Such a method results in furtherenhanced glycemic control and increased weight loss.

Treatment of Diabetes and Improvement of Glycemic Control

In another embodiment, the invention provides a method of treatingdiabetes or improving glycemic control in a subject in need thereof. Themethod comprises the step of orally administering to the subject fromabout 0.7 to about 4 g of crosslinked carboxymethylcellulose peradministration. In one embodiment, the method is conducted prior to orconcurrently with at least one meal per day. In certain embodiments, themethod is conducted prior to or with two meals per day. In certainembodiments, the method is conducted prior to or with three meals perday. In certain embodiments, the subject is directed to eat four or moremeals per day, and the method is conducted prior to or with at least onemeal and up to every meal per day.

In one embodiment, the amount of crosslinked carboxymethylcelluloseadministered with or prior to the meal is from about 1.0 g to about 3.5g. In certain embodiments, the amount of crosslinkedcarboxymethylcellulose administered with or prior to the meal is from1.1 to about 3.5 g or about 1.5 g to 3.5 g. In certain embodiments, theamount of crosslinked carboxymethylcellulose administered with or priorto the meal is from 1.75 g to 3.25 g, or from 2.0 g to 3.0 g. In certainembodiments, the amount of crosslinked carboxymethylcelluloseadministered with or prior to the meal is from 2.15 to 2.35 g. Incertain embodiments, the amount of crosslinked carboxymethylcelluloseadministered with or prior to the meal is about 2.25 g.

In one embodiment, the method is conducted with or prior to one meal perday and the daily amount of crosslinked carboxymethylcelluloseadministered is from about 1.1 g to about 2.25 g. In one embodiment, themethod is conducted with or prior to two meals per day and the dailyamount of crosslinked carboxymethylcellulose administered is from about1.1 g to about 4.5 g, preferably from about 2.2 g to 4.5 g. In oneembodiment, the method is conducted prior to three meals per day and thedaily amount of crosslinked carboxymethylcellulose administered is fromabout 1.65 g to about 6.75 g, preferably from about 3.3 g to about 6.75g. In one embodiment, the method is conducted with or prior to fourmeals per day and the daily amount of crosslinked carboxymethylcelluloseadministered is from about 2.2 g to about 6 g, preferably from about 4.4g to about 6 g.

The crosslinked carboxymethylcellulose can be administered with orwithout water. Typically, the crosslinked carboxymethylcellulose isadministered with at least sufficient water to facilitate swallowing ofthe crosslinked carboxymethylcellulose. In certain embodiments, thecrosslinked carboxymethylcellulose is administered with a volume ofwater in excess of the amount required for swallowing the crosslinkedcarboxymethylcellulose. In one embodiment, about 50 mL to about 250 mLof water per gram of crosslinked carboxymethylcellulose is administered.In certain embodiments the amount of water administered is from about125 mL to about 225 mL per gram of crosslinked carboxymethylcellulose.In other embodiments, the amount of water administered is from about 150mL to about 200 mL per gram of crosslinked carboxymethylcellulose. Incertain embodiments, the amount of water administered is from about 250mL to about 750 mL. In certain embodiments, the amount of wateradministered is from 300 mL to 650 mL, from 350 mL to 600 mL or from 500mL to 550 mL. In certain embodiments, the amount of water administeredis about 500 mL.

The water administered can be flat or carbonated water, or in the formof a beverage. Preferably, non-carbonated water is administered. Inembodiments in which the water is administered as a beverage, thebeverage preferably has a pH of 3 or greater, more preferably a neutralpH, i.e., a pH between 6 and 8, for example, a pH of about 6.5 to about7.5, or about 7. Preferably, the beverage has an energy content in thevolume administered of 100 kilocalories or less or 50 kilocalories orless. Preferably, the beverage is sugar free. In a preferred embodiment,the water is administered as drinking water, for example, tap water,spring water or purified water.

In one embodiment, the crosslinked carboxymethylcellulose isadministered from the beginning of the meal up to 1 hour prior to themeal, from 0 to 40 minutes, from 5 to 35 minutes prior to the meal orfrom 10 to 30 minutes prior to the meal. In another embodiment, thecrosslinked carboxymethylcellulose is administered immediately beforethe meal or with the meal.

In an embodiment, the method is conducted daily up to one week, up tofour weeks, up to eight weeks, up to twelve weeks, up to sixteen weeks,up to twenty weeks, up to twenty-four weeks, up to 36 weeks, or up toone year or longer. In some embodiments, the method is conductedchronically, i.e., for a period of greater than one year or for anindefinite period. In some embodiments, the method is conducted dailyfor a first period of time, stopped for a second period and thenconducted for a third period of time. This alternation of treatmentperiods and nontreatment periods can be conducted over multiple cyclesor continued indefinitely. The treatment period selected will depend onthe needs of the subject, for example, as determined by the treatingphysician.

The subject to be treated is a human or a nonhuman, such as a nonhumanmammal. Suitable nonhuman mammals include domesticated mammals, such aspets, including dogs and cats. Preferably, the subject is a human. Thesubject can be male or female. The human subject can be any age, forexample, a child, an adolescent or an adult. In one embodiment, thesubject is at least 10 or at least 12 years of age. In anotherembodiment, the subject is at least 18 years of age. The subject can be,for example, a human subject suffering from diabetes or at risk ofdeveloping diabetes, for example a subject diagnosed with prediabetes.When the subject is a child, the dose of crosslinkedcarboxymethylcellulose is preferably decreased in proportion with thesubject's size.

In one embodiment, the human subject is prediabetic, as described above.In another embodiment, the subject is diabetic, as described above.

In another embodiment, the subject has an elevated fasting blood glucoselevel, for example, a fasting blood glucose level of about 90 mg/dL orhigher or about 93 or 95 mg/dL or higher. Subjects with fasting bloodglucose levels in this range include those with fasting blood glucoselevels in the high end of normal (90 to under 100 mg/dL), prediabetics(fasting blood glucose levels of 100 to 125.9 mg/dL) and diabetics(fasting blood glucose levels of 126 mg/dL or higher).

The subject can be normal weight, overweight or obese. In certainembodiments, the improvement in glycemic control and/or the symptoms ofdiabetes is accompanied by weight loss, for example, of about 5% ofbaseline body weight or more. In other embodiments, the improvement inglycemic control and/or the symptoms of diabetes is accompanied byweight loss, for example, of less than about 5% of baseline body weight.In still other embodiments, the improvement in glycemic control and/orthe symptoms of diabetes is accompanied by no or insignificant weightloss.

It is to be understood that the measurements described above arebaseline measurements, that is the values of the disclosed physiologicalparameters prior to the commencement of the method of treatmentdescribed herein. Preferably, one or more of the disclosed parametersare determined prior to the commencement of treatment with thecrosslinked carboxymethylcellulose. More preferably, one or more ofthese values are determined within six months of the beginning oftreatment, more preferably within three months and most preferablywithin about one month.

Crosslinked Carboxymethylcellulose

Carboxymethylcellulose can be chemically crosslinked using any methodwhich results in the formation of a biocompatible product havingsufficient absorption and mechanical properties for use in the presentmethod. For example, the carboxymethylcellulose can be crosslinked witha multifunctional cross linking agent or with radiation. In anotherembodiment, the carboxymethylcellulose is crosslinked by formation ofester linkages between polysaccharide strands, for example, by heatingat an acidic pH or by use of a carboxyl activating agent such as acarbodiimide.

In the methods of the invention, the crosslinked carboxymethylcelluloseis administered in a substantially dehydrated state, that is, consistingof less than about 25% water by weight, preferably less that about 20%,15%, 10% or 7% water by weight.

The crosslinked carboxymethylcellulose is preferably a glassy amorphousmaterial when in a substantially dry or xerogel form. In an embodiment,the polymer hydrogels of the invention have a bulk density or a tappeddensity of higher than about 0.3 g/cm³. In preferred embodiments, thebulk density or tapped density is higher than about 0.5 g/cm³ or fromabout 0.55 to about 0.8 g/cm³ when determined as described in USPharmacopeia <616>, incorporated herein by reference. In a preferredembodiment, the bulk or tapped density is about 0.6 g/cm³ or higher, forexample, from about 0.6 g/cm³ to about 0.8 g/cm³.

Preferably the crosslinked carboxymethylcellulose has a water content ofless than about 10% by weight, a tapped density of at least about 0.6g/cm³, an elastic modulus of at least about 350 Pa, and/or a mediauptake ratio of at least about 50 in a 1:8 (vol/vol) mixture ofsimulated gastric fluid (“SGF”, USP 33-28F) and water. More preferablythe crosslinked carboxymethylcellulose has each of the foregoingproperties.

Determination of tapped density, media uptake ratio (MUR) and elasticmodulus can be conducted as described in Example 1.

In a particularly preferred embodiment, the crosslinkedcarboxymethylcellulose is provided as particles which are substantiallyin the size range of 10 μm to 1000 μm. In one embodiment, at least about95% of the crosslinked carboxymethylcellulose by weight consists ofparticles in the size range of 100 μm to 1000 μm or 400 μm to 800 μm.

Preferably, the carboxymethylcellulose is crosslinked starting from asalt, for example, the sodium salt.

In one embodiment, the carboxymethylcellulose is crosslinked with apolycarboxylic acid. Preferably, the carboxymethylcellulose iscrosslinked with citric acid. Suitable methods for crosslinkingcarboxymethylcellulose with citric acid are described in US2013/0089737, WO 2010/059725, WO 2009/022358 and WO 2009/021701, each ofwhich is incorporated herein by reference in its entirety. In oneembodiment, the carboxymethylcellulose is crosslinked via a methodcomprising the steps of (a) producing an aqueous solution orcarboxymethylcellulose and citric acid; (b) removing water from thesolution, for example by evaporation, to produce a solid residue and (c)heat treating the solid residue to form a crosslinkedcarboxymethylcellulose.

In preferred embodiments, the crosslinked carboxymethylcellulose isprepared by a method comprising the following steps: Step 1,carboxymethylcellulose sodium salt and citric acid are dissolved inpurified water to produce a solution essentially consisting of about 5%to about 7%, preferably about 6%, carboxymethylcellulose by weightrelative to the weight of water, and citric acid in an amount of about0.15% to about 0.35% or about 0.15% to about 0.30% by weight relative tothe weight of carboxymethylcellulose; Step 2, maintaining the solutionat a temperature from about 40° C. to about 70° C. or 40° C. to about80° C., preferably about 70° C., to evaporate the water and form a solidcarboxymethylcellulose/citric acid composite; Step 3, grinding thecomposite to form composite particles; and Step 4, maintaining thecomposite particles at a temperature from about 80° C. to about 150° C.or about 100° C. to about 150° C., preferably, about 120° C., for aperiod of time sufficient to achieve the desired degree of cross-linkingand form the polymer hydrogel. The method can optionally further includeStep 5, washing the polymer hydrogel with purified water; and Step 6,drying the purified polymer hydrogel at elevated temperature. A processfor the large scale production of a suitable crosslinkedcarboxymethylcellulose is described in Example 1.

The crosslinked carboxymethylcellulose is preferably crosslinked withcitric acid and has a crosslinked and singly bonded citric acid tocarboxymethylcellulose ratio of 0.05 to 1% wt/wt and more preferably aratio of 0.1 to 0.4% wt/wt. Still more preferably, the crosslinked andsingly bonded citric acid to carboxymethylcellulose ratio is 0.225 to0.375% wt/wt.

The crosslinked carboxymethylcellulose preferably has a degree ofcross-linking from about 2.5×10⁻⁵ mol/cm³ to about 5×10⁻⁵ mol/cm³, morepreferably from about 4×10⁻⁵ mol/cm³ to about 5×10⁻⁵ mol/cm³.

Formulations

The crosslinked carboxymethylcellulose can be administered to thesubject in the form of a tablet, a capsule, a powder, a suspension, asachet or any other formulation suitable for oral administration. Thetablet or capsule can further include one or more additional agents,such as a pH modifying agent, and/or a pharmaceutically acceptablecarrier or excipient. In a preferred embodiment, the crosslinkedcarboxymethylcellulose is loaded into soft or hard gelatin capsules inthe substantial absence of other excipients. Any size capsules can beused; the number of capsules administered per dose will depend on thecapacity of the selected capsule. In one embodiment, the crosslinkedcarboxymethylcellulose is loaded into size 00el soft gelatin capsules inan amount of 0.50 to 1.00 g per capsule, preferably 0.60 to 0.90 g, morepreferably 0.70 to 0.80 g and most preferably about 0.75 g per capsule.

EXAMPLES

The invention now being generally described, it will be more readilyunderstood by the following examples, which are included merely forpurposes of illustration of certain aspects and embodiments of thepresent invention and are not intended to limit the invention.

Example 1 Production of Crosslinked Carboxymethylcellulose

Citric acid crosslinked carboxymethylcellulose (“CMC/CA”) was preparedas described in US Patent Application Publication 2013/0089737,incorporated herein by reference in its entirety. Specifically, sodiumcarboxymethylcellulose (6% wt/wt water), citric acid (0.3% wt/wt sodiumcarboxymethylcellulose) and water was mixed at room temperature andpressure in a low shear mixing vessel until a homogeneous solution isformed. The solution was transferred to trays so as to maintain asolution depth of about 30 mm. The trays were placed in an atmosphericforced air oven and dried for 16 to 24 hours at 85° C. The temperaturewas then lowered to 50° C. until drying was complete. The total dryingtime was about 60 hours. The resulting residue was in the form of asheet, which was ground using a coarse mill and fine mill and sieved toprovide a sample comprising particles of size between 100 and 1600 μm.The particles were placed in a crosslink reactor and maintained at 120°C. and atmospheric pressure for 3 to 10 hours. The resulting hydrogelwas transferred to a wash tank and washed at ambient temperature andpressure with an amount of water between 150 and 300 times the polymerweight. The free water was removed from the hydrogel by filtration. Thehydrogel was placed on trays at a thickness of about 40 mm. The trayswere placed in an atmospheric forced air oven and dried for 24-30 hoursat 85° C. The temperature was then lowered to 50° C. until dry. Thetotal drying time was about 60 hours. The dried material was ground intoparticles using a fine mill and mechanically sieved to obtain particlefractions between 100 and 1000 μm.

Using the general process described above and starting with higher than4 kg of sodium carboxymethylcellulose, the yield was over 70% of powderwith a particle size range between 100 and 1000 μm. The powderedhydrogel product met the product specifications as detailed in the tablebelow.

TABLE 1 Final Product Specifications Attribute Specifications MethodMedia uptake Not Less Than 50x reported 1 g in 200 mL SGF/water as g/g1:8 for 30 minutes Particle size At least 95% of particles Estimation byanalytical distribution between 100 and 1000 μm sieving Tapped densityNot Less Than 0.6 g/mL Bulk density and tapped density of powders.Elastic modulus Not Less Than 350 Pa Analysis of swollen particles withparallel plate rheometer Loss on drying Not More Than 10% Loss on dryingat 100° C. for 20 minutes

The CMC/CA powder was loaded into gelatin capsules in an amount of 0.75g per capsule.

The CMC/CA powder was characterized according to the methods below.

Preparation of Simulated Gastric Fluid/Water (1:8)

Reagents used for preparation of SGF/water (1:8) solution are purifiedwater, sodium chloride, 1M hydrochloric acid and pepsin.

-   1. To a 1 L graduated cylinder pour about 880 ml of water.-   2. Place the cylinder on a magnetic stirrer, add a magnetic bar and    start stirring.-   3. Begin monitoring the pH of the water with a pH meter.-   4. Add a sufficient amount of 1M hydrochloric acid to bring the pH    to 2.1±0.1.-   5. Add 0.2 g NaCl and 0.32 g pepsin. Leave the solution to stir    until complete dissolution.-   6. Remove the magnetic bar and the electrode from the cylinder.-   7. Add the amount of water required to bring the volume to 900 ml.

Determination of Tapped Density

-   Equipment and materials:-   100 mL glass graduated cylinder,-   100 mL glass beaker,-   Lab spatula,-   Mechanical tapped density tester, Model JV 1000 by Copley    Scientific,-   Calibrated balance capable of weighing to the nearest 0.1 g.

Procedure

-   1. Weigh out 40.0±0.1 grams of test sample. This value is designated    M.-   2. Introduce the sample into a dry 100 mL glass graduated cylinder.-   3. Carefully level the powder without compacting and read the    unsettled apparent volume, V0, to the nearest graduated unit.-   4. Set the mechanical tapped density tester to tap the cylinder 500    times initially and measure the tapped volume, V500, to the nearest    graduated unit.-   5. Repeat the tapping 750 times and measure the tapped volume, V750,    to the nearest graduated unit.-   6. If the difference between the two volumes is less than 2%, V750    is the final tapped volume, Vf, otherwise repeat in increments of    1250 taps, as needed, until the difference between succeeding    measurements is less than 2%.

Calculations

-   Calculate the Tapped Density, DT, in gram per mL, by the formula:

DT=M/Vf

-   where:

M=Weight of sample, in grams, rounded off to the nearest 0.1 g.

Vf=Final volume, in mL.

Determination of Media Uptake Ratio in SGF/Water (1:8)

The media uptake ratio of a crosslinked carboxymethylcellulose inSGF/water (1:8) is determined according to the following protocol.

-   1. Place a dried fitted glass funnel on a support and pour 40.0±1.0    g of purified water into the funnel.-   2. Wait until no droplets are detected in the neck of the funnel    (about 5 minutes) and dry the tip of the funnel with an absorbent    paper.-   3. Place the funnel into an empty and dry glass beaker (beaker #1),    place them on a tared scale and record the weight of the empty    apparatus (W_(tare)).-   4. Put a magnetic stir bar in a 100 mL beaker (beaker #2); place    beaker #2 on the scale and tare.-   5. Add 40.0±1.0 g of SGF/Water (1:8) solution prepared as described    above to beaker #2.-   6. Place beaker #2 on the magnetic stirrer and stir gently at room    temperature.-   7. Accurately weigh 0.250±0.005 g of crosslinked    carboxymethylcellulose powder using a weighing paper (W_(in)).-   8. Add the powder to beaker #2 and stir gently for 30±2 min with the    magnetic stirrer without generating vortices.-   9. Remove the stir bar from the resulting suspension, place the    funnel on a support and pour the suspension into the funnel,    collecting any remaining material with a spatula.-   10. Allow the material to drain for 10±1 min.-   11. Place the funnel containing the drained material inside beaker    #1 and weigh it (W′_(fin)).-   The Media Uptake Ratio (MUR) is calculated according to:

MUR=(W _(fin)−W _(in))/W _(in).

-   W_(fin) is the weight of the swollen hydrogel calculated as follows:

W_(fin)=W′_(fin)−W_(tare),

-   W_(in) is the weight of the initial dry sample.-   The MUR is determined in triplicate for each sample of crosslinked    carboxymethylcellulose and the reported MUR is the average of the    three determinations.

Determination of Elastic Modulus

The elastic modulus (G′) is determined according to the protocol setforth below. The rheometer used is a Rheometer Discovery HR-1 (5332-0277DHR-1) by TA Instruments or equivalent, equipped with a Peltier Plate; aLower Flat plate Xhatch, 40 mm diameter; and an Upper Flat plate Xhatch,40 mm diameter.

-   1. Put a magnetic stir bar in a 100 mL beaker.-   2. Add 40.0±1.0 g of SGF/Water (1:8) solution prepared as described    above to the beaker.-   3. Place the beaker on the magnetic stirrer and stir gently at room    temperature.-   4. Accurately weigh 0.250±0.005 g of crosslinked    carboxymethylcellulose powder using a weighing paper (W_(in)).-   5. Add the powder to the beaker and stir gently for 30±2 min with    the magnetic stirrer without generating vortices.-   6. Remove the stir bar from the resulting suspension, place the    funnel on a support and pour the suspension into the funnel,    collecting any remaining material with a spatula.-   7. Allow the material to drain for 10±1 min.-   8. Collect the resulting material.-   9. Subject the material to a sweep frequency test with the rheometer    and determine the value at an angular frequency of 10 rad/s.-   The determination is made in triplicate. The reported G′ value is    the average of the three determinations.

Example 2 Clinical Study of Crosslinked Carboxymethylcellulose

A clinical study of the CMC/CA formulation described in Example 1 wasconducted.

-   Study design: a 12-week study to determine the effect of repeated    administration of CMC/CA on body weight in overweight and obese    subjects. The study was conducted at five European sites. One    hundred twenty-eight subjects, with a mean BMI of 31.7, were    randomized into three arms: CMC/CA 2.25 g, CMC/CA 3.75 g, and    placebo. Subjects ingested either CMC/CA or placebo 30 minutes    before lunch and dinner with two glasses of water. The placebo    capsules contained microcrystalline cellulose, a non-digestible    fiber and bulking agent with low water absorption capacity and    potential weight-loss properties. All subjects received dietary    counseling designed to reduce their calorie intake by 600 kcal/day    below their daily requirement. One hundred twenty-five subjects had    at least one post-baseline assessment of body weight    (intention-to-treat “ITT” population). Forty-two of the ITT subjects    were on CMC/CA 2.25 g, 41 on CMC/CA 3.75 g, and 42 on placebo. One    hundred ten subjects completed the key visit of the study at Day 87    for the assessment of body weight. One hundred twenty-six subjects    provided post-randomization safety data through Day 87. The primary    efficacy endpoint of change in body weight from baseline was    assessed by analysis of the covariance (ANCOVA) model in the ITT    population with baseline weight, gender, and BMI status as    covariates (possible predictors of the outcome).

Efficacy Endpoints

-   Primary: Body weight (Week 13)-   Secondary: Body weight responders (5% weight loss) (Week 13); waist    circumference (Week 13); fat mass and bone-free fat-free mass (DEXA)    (Week 13); appetite (visual analogue scales) (Week 12); food intake    (24-h dietary recall) (Week 12).

Study Duration

-   12-week treatment period plus 10-day post-treatment follow-up    period.

TABLE 2 Sample Size & Power Parameter Value Power  90% Significance0.025 level One-versus One-sided two-sided Placebo-adjusted   2% weightloss Standard 2.5% deviation

TABLE 3 Characteristics of Intention to Treat Population CMC/CA CMC/CAPlacebo 2.25 g 3.75 g All Arms Parameter (n = 42) (n = 42) (n = 41) (n =125) Male (n) 13 (31%) 13 (31%) 14 (34%) 40 (32%) Female (n) 29 (69%) 29(69%) 27 (66%) 85 (68%) Age (years) 44.0 ± 11.7 42.4 ± 12.3 46.1 ± 11.244.2 ± 11.7 BMI 32.0 ± 2.3  31.2 ± 2.3  31.8 ± 2.5  31.7 ± 2.4 Overweight (n) 12 (29%) 13 (31%) 12 (29%) 37 (30%) Obese (n) 30 (71%) 29(69%) 29 (71%) 88 (70%) Glucose 5.31 ± 0.58 5.18 ± 0.54 5.20 ± 0.50 5.23± 0.54 (mmol/L)

Results

-   The results of the study are set forth in Table 4, below, and in    FIGS. 1 to 4.

TABLE 4 Intention to Treat Population CMC/CA CMC/CA: Placebo 2.25 g 3.75g Type of Response (n = 42) (n = 42) (n = 41) Weight gain  7 (17%) 3(7%)  9 (22%) 0 < Weight loss < 5% 18 (43%) 21 (50%) 13 (32%) Weightloss ≧5% 17 (40%) 18 (43%) 19 (46%) Weight loss ≧10%  5 (12%) 11 (26%) 5 (12%)The results show that subjects in the low dose CMC/CA arm had a lowerrate of weight gain and a higher rate of weight loss of 10% or morecompared to the placebo and high dose CMC/CA groups. As shown in FIG. 1and Table 5 below, repeated administration of low dose CMC/CA over 12weeks to overweight and obese subjects resulted in significantlydecreased body weight compared to placebo without reaching a plateau.Weight loss in this group was also significantly greater than in thehigh dose CMC/CA group. Weight loss was greater in the low dose CMC/CAarm for subjects with higher than median fasting blood glucose (>5.15mmol/L (>93 mg/dL)) at baseline, especially in those with impairedfasting blood glucose (≧5.6 mmol/L (≧100 mg/dL)).

Body weight decreased significantly by Day 87 in patients on CMC/CA 2.25g with a placebo-adjusted weight loss of 2.0% and a total body weightloss of 6.1%, while patients in the CMC/CA 3.75 g arm had a total bodyweight loss of 4.5% (0.4% placebo-adjusted). It is believed that thelower observed efficacy in the CMC/CA 3.75 g arm compared with theCMC/CA 2.25 g arm can be explained by two factors: lower tolerabilityand insufficient water intake. Patients in the CMC/CA 3.75 g armreported GI adverse events at a higher rate (76%) than patients in theCMC/CA 2.25 g arm (60%). In addition, 10 patients, or 24%, from theCMC/CA 3.75 g arm dropped out of the study, with 8 of the dropoutsreporting GI AEs, as compared with two patients, or 5%, who dropped outfrom CMC/CA 2.25 g arm, with no GI AEs. When looking specifically at thenonresponders in each arm, in the CMC/CA 3.75 g arm, a statisticallysignificant increase in serum albumin (a surrogate marker forhemoconcentration, which is the decrease of the fluid content of theblood) of 1.8 g/L (p=0.01) is observed, compared with a decrease of 0.3g/L in the placebo arm and a decrease of 0.7 g/L in the CMC/CA 2.25 garm. To maintain a blinded study, the same volume of water was requiredat capsule administration for all arms in the trial. The assumption wasthat the volume of water administered with the capsules, in addition togastric fluids and liquids consumed during the meal, would be sufficientto hydrate both the CMC/CA 2.25 g dose and the CMC/CA 3.75 g dose. Basedon the hemoconcentration observed in the nonresponders in the CMC/CA3.75 g arm, it is believed that these patients did not drink enoughliquids during the meal, resulting in the overall lower weight loss inthis arm. However, although the higher dose of 3.75 g was less effectivefor weight loss possibly due to the reasons mentioned here, it was atleast the same or even more effective for glycemic control.

TABLE 5 Mean % Treatment Arm Weight Change Placebo CMC/CA 2.25 g Placeboadjusted Intent to treat −4.1% (n = 42) −6.1% (n = 42) −2.0% (p = 0.026)population Baseline −4.4% (n = 22) −8.2% (n = 21) −3.8% (p = 0.006)fasting blood glucose >93 mg/dL Baseline −5.6% (n = 11) −10.9% (n = 9) −5.3% (p = 0.019) fasting blood glucose ≧100 mg/dL

As shown in FIGS. 2A and 2B, there was a significant inverse correlationbetween fasting blood glucose level at baseline and change in bodyweight in CMC/CA 2.25 g arm (r=−0.50; P<0.001), contrasting with a lackof correlation in the placebo arm (r=−0.06; P=0.708).

FIGS. 3 and 4 show respectively conversion of obese status to overweightstatus (% of subjects) and conversion of overweight status to normalweight status in the study subjects (% of subjects) in the placebo,CMC/CA 2.25 g and CMC/CA 3.75 g groups.

FIGS. 5-8 and the data in Tables 6 and 7 illustrate the effect oftreatment with CMC/CA on glycemic control and markers of diabetes andprediabetes. FIG. 5 shows the conversion of impaired fasting bloodglucose status to normal fasting blood glucose status (% of subjects) inthe intent to treat population. FIG. 6 shows the change in serum insulinlevels (% change from baseline) over the course of the study. Asignificant decrease in serum insulin relative to placebo was observedin the CMC/CA 3.75 g arm. FIG. 7 shows the decrease of insulinresistance in the intent to treat population, as determined byhomeostatic model assessment. A significant decrease in insulinresistance compared to placebo was observed in both CMC/CA arms. FIG. 8shows the change in glucose levels (% change from baseline) over thecourse of the study. The results show that treatment with CMC/CA 2.25 gsignificantly improved glycemic control.

Table 6 shows the baseline glycemic control parameters in the intent totreat population. The population included subjects with normal andimpaired fasting blood glucose levels but no diabetic subjects. Table 7shows the glucose status in the intent to treat population.

TABLE 6 CMC/CA 2.25 g CMC/CA 3.75 g All Arms Parameter Placebo (n = 42)(n = 42) (n = 41) (n = 125) Insulin (mU/l) 7.7 ± 4.1 6.7 ± 3.1 8.2 ± 3.97.5 ± 3.7 HOMA-IR 1.9 ± 1.1 1.6 ± 0.7 1.9 ± 1.0 1.8 ± 1.0 Glucose 5.31 ±0.58 5.18 ± 0.54 5.20 ± 0.50 5.23 ± 0.54 (mmol/L) High glucose* 22 21 1962 (n) Low glucose** 20 21 22 63 (n) HbA1c 42 ± 5  40 ± 4  42 ± 4  41 ±4  (mmol/mol) *>93 mg/dL; **≦93 mg/dL

TABLE 7 Number of Subjects Placebo CMC/CA 2.25 CMC/CA 3.75 GlucoseStatus (n = 42) g (n = 41) g (n = 39) Impaired glucose (baseline) 11(26%) 9 (22%)  9 (23%) Impaired glucose (end of 12 (29%) 5 (12%) 3 (8%)study) Conversion of normal  4 (10%) 1 (2%)  2 (5%) glucose to impairedglucose (end of study) Conversion of impaired 0 0 1 (3%) glucose todiabetic glucose (end of study) Conversion of impaired 3 (7%) 5 (12%)  7(18%) glucose to normal glucose (end of study)

FIGS. 9 and 10 illustrate the effect of treatment on energy intake insubjects with elevated fasting blood glucose at baseline. FIG. 9 showsthe change in total energy intake in the placebo, CMC/CA 2.25 g andCMC/CA 3.75 g groups. Total energy intake decreased in both CMC/CAgroups compared to placebo, with the greatest decrease shown in theCMC/CA 2.25 g group. FIG. 10 shows the change in energy intake fromcarbohydrate, fat and protein in the placebo, CMC/CA 2.25 g and CMC/CA3.75 g groups. Energy intake from carbohydrate decreased in both CMC/CAgroups, but increased in the placebo group. Energy intake from fatdecreased in all groups, while energy from protein increased more in theCMC/CA groups than in the placebo group.

Both doses of CMC/CA were found to be safe and the 2.25 g dose was verywell tolerated.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A method for treating overweight or obesity in a subject in needthereof, comprising the steps of: (a) orally administering to thesubject from about 0.7 g to about 4 g of a crosslinkedcarboxymethylcellulose; (b) orally administering to the subject at least100 mL water per gram of the crosslinked carboxymethylcellulose; whereinsaid steps (a) and (b) are conducted prior to or with a meal.
 2. Themethod of claim 1, wherein the amount of crosslinkedcarboxymethylcellulose administered in step (a) is from about 1.1 g toabout 3.0 g, from about 1.25 g to 3 g, from about 1.5 g to about 3 g,1.8 g to 3 g or from about 1.75 g to about 2.75 g.
 3. The method ofclaim 2, wherein the amount of crosslinked carboxymethylcelluloseadministered in step (a) is about 2.25 g.
 4. The method of claim 1,wherein the subject has a body mass index of 30 or higher.
 5. The methodof claim 1, wherein the subject has a fasting blood glucose level of 90mg/dL or higher.
 6. The method of claim 1, wherein the subject has afasting blood glucose level of 95 mg/dL or higher.
 7. The method ofclaim 1, wherein the subject has a fasting blood glucose level in therange of 100 to 125.9 mg/dL.
 8. The method of claim 1, wherein thesubject has a fasting blood glucose level of 126 mg/dL or higher.
 9. Themethod of claim 1, wherein the amount of water administered in step (b)is at least about at least about 125 mL per gram of crosslinkedcarboxymethylcellulose.
 10. The method of claim 1, wherein the amount ofwater administered in step (b) is at least about at least about 150 mLper gram of crosslinked carboxymethylcellulose.
 11. The method of claim1, wherein the crosslinked carboxymethylcellulose is characterized byone or more of: (a) a tapped density of at least about 0.6 g/mL; (b) anelastic modulus of at least about 350 Pa, and (c) a media uptake ratioof at least about 50 in a 1:8 mixture of simulated gastric fluid andwater.
 12. The method of claim 11, wherein the crosslinkedcarboxymethylcellulose is characterized by all of (a), (b) and (c). 13.The method of claim 12, wherein the water content of the crosslinkedcarboxymethylcellulose is 25% wt/wt or less, 20% wt/wt or less, 15%wt/wt or less or 10% wt/wt or less.
 14. The method of claim 1, whereinthe carboxymethylcellulose is crosslinked with citric acid.
 15. Themethod of claim 14, wherein the crosslinked carboxymethylcellulose isproduced by a method comprising the steps of: (a) providing a solutionof carboxymethylcellulose sodium salt and citric acid in water, saidsolution consisting essentially of about 5% to about 7%carboxymethylcellulose by weight relative to the weight of the water andcitric acid in an amount of about 0.15% to about 0.35% by weightrelative to the weight of the carboxymethylcellulose; (b) maintainingthe solution at a temperature from about 40° C. to about 80° C., toevaporate the water and form a substantially dry solid residue; (c)grinding the residue to form residue particles; and (d) heating theresidue particles to a temperature from about 80° C. to about 150° C.for a period of time sufficient to crosslink the carboxymethylcellulose.16. (canceled)
 17. A method for treating diabetes or improving glycemiccontrol in a subject in need thereof, comprising the step of orallyadministering to the subject from about 0.7 g to about 4 g ofcrosslinked carboxymethylcellulose prior to or concurrently with a meal.18. The method of claim 17, wherein the amount of crosslinkedcarboxymethylcellulose administered is from about 1.0 g to 3.5 g, about1.1 g to about 3.5 g or from about 1.5 g to about 3.5 g.
 19. The methodof claim 17, wherein the amount of crosslinked carboxymethylcelluloseadministered is about 2.25 g.
 20. The method of claim 17, wherein thesubject is prediabetic.
 21. The method of claim 20, wherein the subjecthas a fasting blood glucose level from 100 to 125.9 mg/dL.
 22. Themethod of claim 17, wherein the subject has a fasting blood glucoselevel of 126 mg/dL or higher.
 23. The method of claim 17, furthercomprising administering to the subject water in an amount of about 50mL to 250 mL per gram of crosslinked carboxymethylcelluloseadministered.
 24. The method of claim 23, wherein the amount of wateradministered is about 500 mL.
 25. The method of claim 17, wherein thecrosslinked carboxymethylcellulose is characterized by one or more of:(a) a tapped density of at least about 0.6 g/mL; (b) an elastic modulusof at least about 350 Pa, and (c) a media uptake ratio of at least about50 in a 1:8 mixture of simulated gastric fluid and water.
 26. The methodof claim 25, wherein the crosslinked carboxymethylcellulose ischaracterized by all of (a), (b) and (c).
 27. The method of claim 26,wherein the water content of the crosslinked carboxymethylcellulose issubstantially dehydrated.
 28. The method of claim 17, wherein thecarboxymethylcellulose is crosslinked with citric acid.
 29. The methodof claim 28, wherein the crosslinked carboxymethylcellulose is producedby a method comprising the steps of: (a) providing a solution ofcarboxymethylcellulose sodium salt and citric acid in water, saidsolution consisting essentially of about 5% to about 7%carboxymethylcellulose by weight relative to the weight of the water andcitric acid in an amount of about about 0.15% to about 0.35% by weightrelative to the weight of the carboxymethylcellulose; (b) maintainingthe solution at a temperature from about 40° C. to about 80° C., toevaporate the water and form a substantially dry solid residue; (c)grinding the residue to form residue particles; and (d) heating thecomposite particles to a temperature from about 80° C. to about 150° C.for a period of time sufficient to crosslink the carboxymethylcellulose.30. (canceled)
 31. A method for inducing weight loss in a subject havingelevated blood glucose at baseline comprising the step of orallyadministering to the subject an effective amount of a gelling agent. 32.The method of claim 31, wherein the subject has a fasting blood glucoselevel of 90 mg/dL or greater.
 33. The method of claim 31, wherein thesubject has a fasting blood glucose level of 95 mg/dL or greater. 34.The method of claim 31, wherein the subject has a fasting blood glucoselevel of 100 to 125.9 mg/dL.
 35. The method of claim 31, wherein thesubject has a fasting blood glucose level of 126 mg/dL or higher. 36.The method of claim 31, wherein the gelling agent is a fiber or ahydrogel.
 37. The method of claim 36, wherein the hydrogel is asuperabsorbent polymer.
 38. The method of claim 31, wherein the gellingagent is a polysaccharide or a synthetic polymer.
 39. The method ofclaim 38, wherein the polysaccharide is selected from glucans,hemicelluloses, alactomannans, pectins, fructans, seaweed gums, chitin,chitosan, and glycosaminoglycans.
 40. The method of claim 38, whereinthe polysaccharide is selected from alpha-glucans and beta glucans. 41.The method of claim 38, wherein the polysaccharide is selected fromstarch, dextran, pullulan, glycogen, cellulose, cellulose derivatives,carboxymethylcellulose, hydroxyethylcellulose, methylcellulose,chrysolaminarin, curdlan, laminarin, lentinan, lichenin, pleuran,zymosan, glucomannan, arabinoxylan, xylan, glucuronoxylan, xyloglucan,guar gum, fenugreek gum, tara gum, locust bean gum, inulin, levan,alginates, algal polysaccharides, agar, carrageenan; chitin, chitosan,hyaluronic acid, heparin, heparan sulfate, chondroitin sulfate, dermatansulfate, and keratan sulfate.
 42. The method of claim 31, wherein thegelling agent is crosslinked carboxymethylcellulose.
 43. The method ofclaim 42, wherein the carboxymethylcellulose is crosslinked with citricacid.
 44. The method of claim 38, wherein the synthetic polymer isselected from the group consisting of poly(ethylene glycol) basedpolymers, acrylates and acrylate copolymers, combinations of gums withhydrophilic polymers; absorbent polypeptides; polyvinyl andpolyallyl-alcohol systems; crosslinked polyvinyl pyrrolidone;polyamines; absorbent dendrimers; and poly(lactic acid),polyhydroxyalkanoates, polyvinyl acetatephthalate and copolymers andcombinations thereof.
 45. The method of claim 38, wherein the syntheticpolymer is selected from the group consisting ofpolyacrylate/polyalcohol copolymers, polyacrylate/polyacrylamidecopolymers, crosslinked sodium polyacrylate; polyalcohol polymers, andcombinations thereof; polyacrylamide and acrylamide-based products;combinations of polyisobutylene or styrene butadiene rubber withhydrophilic polymers; polyvinylacetate/vinylalcohol copolymers,crosslinked polyvinyl pyrrolidone; polyallyl amine, cross-linked with apolyolefin; poly(lactic acid), polyhydroxyalkanoates, polyvinylacetatephthalate and copolymers and combinations thereof.